Protective effects of hydroxychloroquine against accelerated atherosclerosis in systemic lupus erythematosus

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Review Article

Protective Effects of Hydroxychloroquine against Accelerated

Atherosclerosis in Systemic Lupus Erythematosus

Alberto Floris

,

1

Matteo Piga

,

1

Arduino Aleksander Mangoni

,

2

Alessandra Bortoluzzi

,

3

Gian Luca Erre

,

4

and Alberto Cauli

1

1_{Rheumatology Unit, University Clinic and AOU of Cagliari, Monserrato, Italy}

2_{Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University and Flinders Medical Centre,}

Adelaide, Australia

3_{Department of Medical Sciences, Section of Rheumatology, University of Ferrara and Azienda Ospedaliero-Universitaria Sant}_’Anna

di Cona, Ferrara, Italy

4_{Rheumatology Unit, Department of Clinical and Experimental Medicine, University Hospital (AOUSS) and University of Sassari,}

Sassari, Italy

Correspondence should be addressed to Alberto Floris; albertoﬂoris1@gmail.com Received 28 July 2017; Accepted 10 December 2017; Published 18 February 2018 Academic Editor: Yona Keisari

Copyright © 2018 Alberto Floris et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cardiovascular (CV) morbidity and mortality are a challenge in management of patients with systemic lupus erythematosus (SLE). Higher risk of CV disease in SLE patients is mostly related to accelerated atherosclerosis. Nevertheless, high prevalence of traditional cardiovascular risk factors in SLE patients does not fully explain the increased CV risk. Despite the pathological bases of accelerated atherosclerosis are not fully understood, it is thought that this process is driven by the complex interplay between SLE and atherosclerosis pathogenesis. Hydroxychloroquine (HCQ) is a cornerstone in treatment of SLE patients and has been thought to exert a broad spectrum of beneficial effects on disease activity, prevention of damage accrual, and mortality. Furthermore, HCQ is thought to protect against accelerated atherosclerosis targeting toll-like receptor signaling, cytokine production, T-cell and monocyte activation, oxidative stress, and endothelial dysfunction. HCQ was also described to have beneficial effects on traditional CV risk factors, such as dyslipidemia and diabetes. In conclusion, despite lacking randomized controlled trials unambiguously proving the protection of HCQ against accelerated atherosclerosis and incidence of CV events in SLE patients, evidence analyzed in this review is in favor of its beneficial effect.

1. Introduction

Systemic lupus erythematosus (SLE) is a chronic

autoim-mune inﬂammatory disease characterized by a broad range

of clinic manifestations and serologic

ﬁndings [1, 2]. The

prevalence of SLE ranges between 28.3 and 149.5 cases per

100,000 people and is higher in females of childbearing

age [3]. Patients with SLE have a 2 to 3 times increased

risk of premature death. Cardiovascular disease (CVD) is

the leading cause of mortality regardless of time after

diag-nosis [4, 5]. The overall risk of myocardial infarction (MI)

in SLE patients is 10-fold higher than that in the general

population; however, it is much greater in young SLE

women aged 35

–44 years old, who are over 50 times more

likely to have a MI, than in age-matched women without

SLE [6, 7]. Noteworthy, the increased awareness of the

burden of CVD in patients with SLE has not yet translated

into decreased rates of hospitalization for acute MI or

stroke [8, 9].

The higher risk of CVD in SLE patients is mostly related

to accelerated atherosclerosis, which leads to clinical

symp-toms and manifestations at an earlier age compared to the

general population [10]. Despite the pathobiological bases

of accelerated atherosclerosis are not fully understood, it

is thought that this process is driven by the complex

inter-play between autoimmunity, in

ﬂammation, vascular repair,

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traditional risk factors, and therapeutic agents [10, 11]. As

a result, not surprisingly, the traditional Framingham

cardiac risk factors do not fully explain the increased

prev-alence of CVD observed in SLE [6, 12–14]. Moreover,

multiple SLE-related features of autoimmunity have been

associated with accelerated atherosclerosis [10, 11, 15, 16].

Hydroxychloroquine (HCQ) has been used for more

than 50 years in the treatment of SLE patients. Over the last

decades, an increasing number of in vitro and in vivo studies

have highlighted the potential protective e

ﬀect of HCQ

against CVD through multiple mechanisms of action. This

review discusses the role of SLE-related and SLE-unrelated

factors in the pathophysiology of accelerated atherosclerosis,

the pharmacology of HCQ, and the available evidence

regarding the eﬀects of this agent in reducing CV risk in

SLE patients.

2. SLE and Accelerated Atherosclerosis

Roman et al. reported an increased prevalence of

atheroscle-rosis, as determined by ultrasound assessment of carotid

plaques, in patients with SLE (RR 2.4; 95% conﬁdence

inter-val (CI), 1.7–3.6; P < 0 001), particularly in those younger

than 40 years which prevalence was 5.6 times higher than

healthy controls [17]. Similarly, Asanuma et al. found a

signiﬁcantly higher prevalence of coronary calciﬁcation

(OR 9.8, 95%CI 2.5–39.0, P = 0 001) and greater coronary

artery calcium scores (

P < 0 001) in SLE patients than in

healthy controls [18].

Longer disease duration (OR 2.14, 95%CI 1.28

–3.57;

P = 0 004) and higher disease-related Systemic Lupus

Inter-national Collaborating Clinics (SLICC)/damage index (SDI)

(OR 1.26 per SDI point score, 95%CI 1.03–1.55, P = 0 03)

were identi

ﬁed as independent predictors of carotid plaque

in SLE [17]. In some studies, lupus disease activity was

signiﬁcantly associated with subclinical measures of

athero-sclerosis in univariate analysis, but its independent eﬀect

was not conﬁrmed in multivariate analysis [19–21].

3. Interplay between SLE and Atherogenesis

The increasing evidence that both adaptive and innate

immunity take part in the initiation and progression of

atherosclerosis suggests that the dysregulation of the immune

system of SLE could play an independent role in

atherogene-sis (Table 1) [22].

3.1. Endothelial Dysfunction. Endothelial dysfunction is

one of the earliest signs of atherosclerosis [16, 23],

result-ing in increased expression of adhesion molecules and

impaired vasodilation [24]. A recent meta-analysis, of 25

case-control studies involving 1313 SLE patients and 1012

healthy controls, con

ﬁrmed that patients with SLE who are

naïve of cardiovascular disease have impaired endothelial

function as determined by brachial artery

ﬂow-mediated

dilation [25].

An imbalance between circulating apoptotic

endothe-lial cells (ECs), indicative of vascular damage, endotheendothe-lial

progenitor cells (EPCs), and circulating myelomonocytic

angiogenic cells (CACs), expression of vascular repair

mechanisms, was described in SLE patients [26, 27]. Such

ﬁndings correlate with the presence of endothelial

dysfunc-tion (beta =

−4.5, P < 001) assessed by brachial artery

ﬂow-mediated dilation [26].

Both endothelial damage and the initiation of the

athero-genic process are inﬂuenced by the redox environment.

Table 1: Possible protective eﬀects of HCQ on the interplay between atherosclerosis and SLE pathogenesis.

Features of SLE pathogenesis HCQ Features of atherosclerosis pathogenesis

Imbalance between endothelial damage

and repair mechanisms Endothelial dysfunction

Increased oxidative stress Endothelial damage and impaired vasodilatation

Increased macrophage activation Monocyte recruitment and activation in atherosclerotic plaques

Hyperactive T-cell with increased survival T-cell recruitment and activation in atherosclerotic plaques Dysregulation of TLR2 and TLR4 activation;

activation of TLR7 and TLR9 by anti-DNA Overexpression and activation of TLRs (especially TLR2/TLR4)

Increased levels of IFNα Increased activation of macrophages and foam cells

in the atherosclerotic plaques

Increased levels of TNF-α, IL-17, IL-6 Increased macrophage activation, adhesion molecule expression, chemotaxis, and inhibition of SMC proliferation

Increased levels of IFN-γ Increased expression of adhesion molecule expression and

inhibition of SMC proliferation and collagen production Increased prevalence of anti-ApoA-1

antibodies and proinﬂammatory HDL Decreased antiatherosclerosis HDL function

The arrows represent the interplay between SLE and atherogenesis. The crosses represent the proved (black) or potential (blank) action of HCQ in inhibiting the proatherogenic eﬀect of SLE.

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Patients with SLE have increased concentrations of reactive

oxygen species (ROS) and decreased antioxidant defense

mechanisms which provide a favorable environment for

oxidation of lipoproteins and atherosclerosis development

[28, 29]. Moreover, a positive correlation between SLE

dis-ease activity and oxidative stress was observed in some

studies [28, 30, 31], but not in others [32, 33].

Further potential mechanisms involved in endothelial

dysfunction in SLE include alterations in lipid proﬁle with

increased oxidized LDL (ox-LDL) and proinﬂammatory

high-density lipoproteins (HDL) [11], high frequency of

low-density granulocytes (LDG) with direct toxic eﬀect on

the endothelium [34], renal involvement, and

antiphospholi-pid antibodies [35, 36].

3.2. Monocytes and T-Cell Recruitment and Activation.

Due to the overexpression of adhesion molecules and the

increased chemokine releasing by activated ECs,

mono-cytes can migrate into the intima and diﬀerentiate into

macrophages. The uptake of ox-LDL by scavenger

recep-tors leads to a further transformation into foam cells that

secrete proinﬂammatory cytokines under the toll-like

receptor (TLR) stimuli [22]. Macrophage activation, as

assessed by serum neopterin measurement, was

demon-strated to be increased in SLE patients (median (IQR) serum

neopterin nmol/L: 8.0 (6.5

–9.8) versus 5.7 (4.8–7.1) in SLE

and healthy controls, resp.) [37] and to correlate with

SLE disease activity [38, 39]. However, a signi

ﬁcant

associ-ation with coronary calcium in SLE patients was not

observed [37].

T-cells, consisting predominately of CD4+ T helper 1,

are recruited to nascent atherosclerotic plaques similarly

to monocytes and represent approximately 7–17% of the

cells in the lesion [40]. T-cells have been shown to be

hyperactive in lupus patients, with reduced apoptosis rate

and increased survival [41

–43]. In support of the role of

CD4+ T-cells in the link between SLE and atherosclerosis,

Stanic et al. demonstrated an increased in

ﬁltration of

CD4+ T-cells into the atherosclerotic lesions of LDLr

−/−

mice following transfer of bone marrow from

lupus-susceptible mice [44].

3.3. Toll-Like Receptors. The toll-like receptors (TLRs), a class

of pattern recognition receptors expressed on multiple cells

involved in innate immunity, were demonstrated to be

involved in atherogenesis [45, 46]. Edfeldt et al. found that

the expression of TLR1, TLR2, and TLR4 was markedly

enhanced in human atherosclerotic plaques [47]. Miller

et al., in their in vitro experiments, reported that the binding

of TLR4 and CD14 to ox-LDL on macrophages inhibits the

phagocytosis of apoptotic cells, upregulates the expression

of the scavenger receptor, and increases the uptake of

ox-LDL [48].

Recent studies described a dysregulated activation of

TLR2 and TLR4 in SLE patients, resulting in upregulated

production of autoantibodies and cytokines [49]. Moreover,

the endogenous anti-DNA antibody immune complexes

typ-ical of SLE can bind TLR7 and TLR9 on active plasmacytoid

dendritic cells (DCs) and promote the release of IFNα. This

leads to the recruitment of activated inﬂammatory cells,

self-perpetuating the process of inﬂammation and plaque

formation [46].

3.4. Cytokines. Many cytokines are involved both in

athero-sclerosis and SLE pathogenesis. IFNα is a multifunctional

cytokine which plays a pivotal role in SLE pathogenesis. IFNα

concentrations are increased in SLE patients, associate with

disease activity [50], and seem to be involved in endothelial

dysfunction. Denny et al. demonstrated that IFN

α induces

EPC and CAC apoptosis and skews myeloid cells toward

nonangiogenic phenotypes, whilst neutralization of IFN

pathways led to a normalization of the EPC/CAC phenotype

[27, 43]. Recently, IFN

α has been claimed to serve as a

proatherogenic mediator through repression of endothelial

NO synthase-dependent pathways promoting the

develop-ment of endothelial dysfunction and cardiovascular disease

in SLE [51].

IFNγ, a key regulator of immune function, was

demon-strated to be highly expressed and to play a crucial role both

in SLE and in atherosclerosis [52, 53]. IFN

γ participates in

atherogenesis by stimulating ECs and macrophage

activa-tion, proin

ﬂammatory mediator production, and

adhesion-molecule expression and by inhibiting smooth muscle cell

proliferation and collagen production [22, 54].

Other cytokines overexpressed in SLE, such as TNF-α,

IL-17, and IL-6, participate in the initiation and

perpet-uation of the atherosclerotic process by stimulating the

activation of macrophages, inducing the secretion of

matrix metalloproteinases, upregulating the expression

of adhesion molecules on the ECs, increasing the

con-centration of chemotactic messengers, and a

ﬀecting the

proliferation of smooth muscle cells [15, 55

–59]. In

SLE, serum TNF-

α concentrations have been reported to

be elevated and to correlate with CVD and altered lipid

pro

ﬁles [60, 61].

3.5. Reduced Protective E

ﬀect of High-Density Lipoproteins.

HDL have atheroprotective e

ﬀects through the inhibition

of oxidative modi

ﬁcation of LDL, stimulation of reverse

cholesterol transport, and attenuation of endothelial

dys-function. During the acute phase of inﬂammation, HDL

can be converted from anti-inﬂammatory to

proinﬂamma-tory molecules that promote LDL oxidation [62, 63].

McMahon et al. found that a higher proportion of SLE

patients had proinﬂammatory HDL (44.7% of SLE patients

versus 4.1% of controls,

P < 0 006 between all groups), which

correlated with ox-LDL concentrations (r = 0 37, P < 0 001)

and coronary artery disease (P < 0 001) [64].

The prevalence of antibodies against apolipoprotein A1

(anti-ApoA-1), the main component of HDL, is signiﬁcantly

higher in patients with acute coronary syndrome (21%) and

in patients with SLE and/or antiphospholipid syndrome

(13

–32%), than in healthy subjects (1%) [65, 66]. Although

the direct demonstration of a cause-e

ﬀect relationship is

needed, the high prevalence of anti-ApoA-1

autoanti-bodies in SLE patients is supposed to play a role in

accelerated atherosclerosis.

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4. Increased Prevalence of Traditional

Cardiovascular Risk Factors in SLE

Some of the traditional risk factors for atherosclerosis,

such as dyslipidemia, diabetes, and hypertension, have an

increased prevalence in SLE patients [67].

4.1. Dyslipidemia. SLE patients exhibit an increased

incidence of proatherogenic lipid proﬁle, consisting in low

concentrations of HDL and high concentrations of

triglycer-ides, total cholesterol, and LDL [43]. The increased

preva-lence of dyslipidemia in SLE may be due to both steroid

therapy and disease-related pathogenetic mechanisms,

including increased C-reactive protein levels, cytokine release

(e.g., TNF-alpha and IL-6), and antibodies against

lipopro-tein lipase (LPL) a

ﬀecting the balance between pro- and

antiatherogenic lipoproteins [68]. In 918 SLE patients of

the Systemic Lupus International Collaborating Clinics

’

cohort, the prevalence of hypercholesterolemia was 36%

at diagnosis and 60% 3 years later [69]. Moreover, in the

same cohort, hypercholesterolemia was signiﬁcantly

associ-ated with CV events (OR = 4.4, 95%CI 1.51–13.99) [70].

4.2. Hypertension. Hypertension is an independent risk factor

CV in SLE (OR 5.0; 95%CI 1.3

–18.2) [70]. In a case-control

study, Bruce et al. reported a 2.59 RR (95%CI 1.79

–3.75) of

hypertension in women with SLE [12]. In a multivariate

anal-ysis, Doria et al. found that hypertension was associated with

atherosclerosis by means of higher carotid intima-media

thickness in SLE patients [21].

4.3. Diabetes and Insulin Resistance. An increased prevalence

of insulin resistance and diabetes was reported in several

studies [70–72], but not in all [73]. Bruce et al. reported a

6.6 RR (95%CI 1.36–26.53) of diabetes, which is an

estab-lished risk factor for CVD, in SLE women [12].

An unbalance in adipokine production, consisting of

lower concentrations of adiponectin and higher

concentra-tions of leptin, was proposed as a potential cause of the

increased prevalence of insulin resistance in SLE, as well as

corticosteroid use [74]. However, neither insulin resistance

nor diabetes has been shown to independently predict CV

events in SLE cohorts [70, 72].

Dyslipidemia, hypertension, and insulin resistance can

be part of metabolic syndrome that was observed to be

more frequent in SLE patients compared with controls

(32.4% versus 10.9%;

P < 0 001) and associated to an

increased risk of atherosclerosis by means of aortic pulse

wave velocity [75, 76].

5. Hydroxychloroquine Pharmacology

HCQ is an antimalarial agent that has been used for many

years in treating inﬂammatory rheumatic diseases, especially

SLE and rheumatoid arthritis. HCQ is administered orally as

the sulphate salt and, being a weakly basic drug, is rapidly

absorbed in the upper gastrointestinal tract with a large

vol-ume of distribution. HCQ is then dealkylated by cytochrome

P450 enzymes into its active metabolite desethyl-HCQ [77].

The systemic clearance is by renal excretion with a long tissue

half-life of 40–50 days. HCQ may take up to 4–6 weeks for

the onset of therapeutic action and 3–6 months to achieve

the maximal clinical eﬃcacy. The recommended dose of

HCQ is 200–400 mg daily or about 5 mg/kg/day in a

weight-based regimen [77]. According to Durcan et al. [78],

HCQ dosing based on actual body weight, instead of ideal

weight, is appropriate for patients with SLE. Blood HCQ

concentrations can be measured with available commercial

kits, which may help in adherence monitoring and the

identi

ﬁcation of individualized therapeutic regimens [79].

HCQ has numerous and complex mechanisms of

action (Figure 1). The increasing pH in the intracellular

compartments (“lysosomotropic action”) favors

HCQ-mediated interference with phagocytosis, receptor recycling,

antibody production, and selective presentation of

self-antigens [67]. Moreover, HCQ blocks T-cell and monocyte

proliferation, inhibits TLR signaling, and downregulates

cytokine production including TNF-alpha, IL-17, IL-6, IFNα,

and IFN

γ [77].

6. Hydroxychloroquine Clinical Benefits in SLE

6.1. Disease Activity. The

ﬁrst study on HCQ clinical eﬃcacy

in SLE randomized 25 patients to continue HCQ on

stable dose therapy and 22 patients to switch to placebo for

24 weeks. A lower rate of

ﬂare (36% versus 73%, P = 0 02;

T-cell proliferation TLR activation cytokines production (TNF훼, IFN훼, and IL-6) self-antigen presentation

antibody production

prostaglandin production platelet aggregation

oxidative stress insulin clearance lipids level Hydroxychloroquine

mechanisms of action

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RR 2.5 95%CI 1.1–5.6) was observed in the HCQ group [80].

More recently, Ruiz-Irastorza et al. systematically reviewed

the eﬀect of HCQ on lupus activity and identiﬁed 8 studies,

of which 3 were randomized controlled trials [81]. All studies

were of high quality and consistently found lupus disease

activity and

ﬂares to be signiﬁcantly reduced in patients

treated with HCQ [81, 82].

6.2. Atherosclerosis. Some studies did not

ﬁnd any eﬀect

of current [20, 83] or past [84–87] treatment with HCQ

on the presence of atherosclerosis. On the other hand,

Roman et al., in multivariate analysis, found a

borderline-independent eﬀect of current or former treatment with

HCQ (adjusted OR 0.49; 95%CI 0.21

–1.12; P = 0 09) in

reducing plaque burden, on carotid ultrasound, of SLE

patients [17]. Moreover, the current use of HCQ was

associ-ated with signi

ﬁcantly lower (partial R2 0.025; P = 0 032)

aortic sti

ﬀness, measured by pulse wave velocity, in

premen-opausal SLE women [88]. Noteworthy, the only study

speciﬁcally designed to analyze the eﬀect of treatment with

HCQ on atherosclerosis, albeit conducted in a relatively

small population (n = 41), found increased large artery

elasticity (13.7 versus 8.3 mmHg

× ml × 10; P = 0 006) and

reduced systemic vascular resistance (14.4 versus 18.4

dyne

× sec × 10

−3

;

P = 0 05) among patients treated with

HCQ compared with those receiving corticosteroids only

[89]. Overall, the available evidence is inconclusive, mainly

as a result of poor study quality and design [81].

6.3. Irreversible Target Organ Damage and Survival. The

beneﬁcial eﬀects of HCQ on target organ damage and

survival in SLE patients have been demonstrated by several

high-quality evidence studies [81, 90–93]. For example,

HCQ was protective (HR 0.73; 95%CI 0.52 to 1.00) against

damage accrual, calculated using the SLICC damage index,

in the prospective LUMINA (Lupus in Minorities: nature

versus nurture) study cohort, particularly in those patients

without damage at baseline (HR 0.55, 95%CI 0.34 to 0.87)

(94). In the same cohort, 17% of patients not taking HCQ

died during the follow-up versus 5% of those treated with

HCQ (P < 0 001), accounting for a 0.28 unadjusted OR

(95%CI 0.05 to 0.30) and 0.32 adjusted OR (95%CI 0.12 to

0.86) [94]. Moreover, HCQ use was associated with less

cerebrovascular damage on brain MRI of SLE patients (OR

0.08; 95%CI 0.01

–0.73) [95], less thrombosis (OR 0.31,

95%CI 0.13

–0.71) [96], less CV events (HR 0.04, 95%CI

0.004 –0.48) [97], and less, albeit not statistically signiﬁcant,

cardiovascular mortality (0% versus 36.8%) [98].

In a multinational Latin American inception cohort, a

lower mortality rate was observed in antimalarial users

compared with nonusers (4.4% versus 11.5%;

P < 0 001),

and, after adjustment for potential confounders in a Cox

regression model, antimalarial use was associated with a

38% reduction in the mortality rate (hazard ratio 0.62,

95%CI 0.39

–0.99) [99].

It remains to be established whether HCQ exerts its

protective e

ﬀects on damage accrual and survival in SLE

patients through lowering disease activity, preventing

atherosclerosis, or both.

7. Hydroxychloroquine and SLE-Related Risk

Factors for Atherosclerosis

7.1. Endothelial Dysfunction. Endothelial dysfunction (ED)

is a potentially reversible alteration thus representing an

attractive target for CVD prevention and treatment.

Gómez-Guzmán et al. [100] found that short-term

treat-ment with HCQ in advanced disease stages is able to

reverse large artery ED in a murine model of SLE. This

eﬀect was mediated by a reduction of nicotinamide

ade-nine dinucleotide phosphate (NAD(P)H) oxidase activity,

which is a major ROS source. Recently, Virdis et al.

con-ﬁrmed that early treatment with HCQ exerts protective eﬀect

by decreasing vascular oxidative stress and improving

endothelium-dependent relaxation, essentially by preserving

the NO-mediated component [101].

7.2. Toll-Like Receptor Signaling and Cytokine Production.

Evidence that HCQ acts by blocking the nucleic

acid-sensing TLRs (TLR3, TLR7, TLR8, and TLR9) is the most

important advance in our understanding of its mechanism

of action. Nucleic-sensing TLRs, located in intracellular

com-partments, are activated when interacting with foreign

nuclear material presented by specialized molecules such as

FC-gamma receptor on DCs or B-cell receptor on the surface

of B-cells. HCQ interferes with the TLR7 and TLR9 signaling

pathways, reducing the production of IFNα, IL-6, and TNF-α

[102]. It has been postulated that, by altering the lysosomal

pH, HCQ prevents TLR functional transformation and

activation [103]. However, it is also possible that, by binding

nucleic acids, HCQ masks their TLR-binding epitope

preventing TLR activation [104].

Beyond the inhibition of TLR signaling, experimental

evidence showed that HCQ reduces the concentration of

proatherogenic cytokines, such as IFNα, IL6, TNF-α, IL17,

and IL22, in SLE patients through diﬀerent mechanisms

[105, 106]. The observation that HCQ reduces the expression

of miR155 in NZB/NZW mice, a SLE animal model, suggests

additional therapeutic eﬀects through an epigenetic control

of cytokine gene expression [107].

7.3. Actions on Immune System Cells and Autoantibody

Production. T-cell and B-cell activities may be directly or

indirectly aﬀected by HCQ [103]. The HCQ “lysosomotropic

action

” is responsible for altering the process of self-antigen

presentation, whilst preserving that of exogenous antigens,

and may also inhibit the intracellular calcium signals after

T-cell-receptor stimulation, preventing T-cell activation

and proliferation [103, 108]. Furthermore, the inhibition

of IFNα, IL6, IL17, and TNF-α production aﬀects B-cell

activation and autoantibody production and favors the

dif-ferentiation of endothelial cells [103].

The reported HCQ-mediated eﬀects may theoretically

reduce the initiation and progression of atherosclerosis by

inhibiting the monocyte adhesion to endothelial cells,

reduc-ing smooth cell proliferation and favorreduc-ing vascular repair.

However, to date, no study has investigated whether the

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preventing atherosclerosis in SLE patients. More research is

warranted to conﬁrm, or refute, this hypothesis.

8. Hydroxychloroquine and Traditional

Atherosclerosis Risk Factor

8.1. Effects on Lipid Profile. The beneficial effect of HCQ on

dyslipidemia in patients with SLE has been known for some

time. Potential mechanism underlying the beneﬁcial eﬀect

of antimalarials on dyslipidemia may be represented by

upregulation of LDL receptors with an enhancement of the

plasma removal of this lipoprotein [109]. This potential

e

ﬀect of antimalarials would minimize the increased

lipo-protein hepatic synthesis induced by steroids [110]. Petri

et al. [111] found that HCQ treatment was independently

associated with lower serum cholesterol concentrations in

multivariate analysis (eﬀect on mg% −8.94; P = 0 009). In

a cohort of 815 patients, Rahman et al. [13] showed that

the lipid lowering eﬀect of antimalarials (mainly HCQ)

was higher in patients on a stable dose of steroids and

consisted of a reduction in total cholesterol concentrations

of 11.3% at 3 months (

P = 0 0002) and 9.4% at 6 months

(

P = 0 004). Contrasting results have been reported on the

di

ﬀerent lipoprotein proﬁles [112–114]. However, two recent

prospective studies speciﬁcally designed to analyze the eﬀect

of HCQ on lipoprotein concentrations, after correction for

the confounding eﬀect of other variables, found lower

LDL (P = 0 036) [113], VLDL (P = 0 002), and triglyceride

concentrations (P = 0 043) and higher HDL concentrations

(P = 0 03) [114] in patients treated with HCQ.

8.2. E

ﬀects on Glucose Level. Hypoglycemia has been reported

in patients treated with antimalarials. In vitro and animal

studies, antimalarials a

ﬀected insulin metabolism, increasing

insulin binding to its receptor, altering hepatic insulin

metabolism, potentiating insulin action, and reducing the

insulin clearance [115

–117]. A small randomized study in

decompensated diabetic patients showed that HCQ

signiﬁ-cantly lowered glycated hemoglobin A1c (3.3%; 95%CI,

−3.9 to −2.7, P = 0 001) when added to insulin therapy,

possibly by improving insulin secretion and peripheral

sensitivity [118].

Recently, the use of HCQ has been associated with lower

concentrations of serum glucose (85.9 versus 89.3 mg/dl,

P = 0 04) [119] and a lower incidence of diabetes mellitus

in SLE patients, in a dose-dependent manner (HR 0.26;

95%CI 0.18–0.37; P < 0 001) [120].

8.3. Eﬀects on Thrombosis. HCQ has a protective eﬀect

against thrombosis both in SLE patients with and without

antiphospholipid antibodies [86]. Such an eﬀect seems

mediated by reduced platelet aggregation and protection of

the annexin A5 anticoagulant shield from disruption by

aPL antibodies [121].

9. Discussion

There is good evidence from prospective studies of an

increased CV risk in SLE patients [4–7]. Accelerated

atherosclerosis, in the presence of traditional risk factors,

may explain at least in part this enhanced risk. However,

SLE-related factors, as endothelial dysfunction and

inﬂam-mation, autoantibodies, damage accrual, and disease activity

are equally or even more important [10

–14]. Such a complex

interplay of pathogenetic mechanisms presents clinical

chal-lenges, particularly because of the lack of data on the e

ﬀects

of the modi

ﬁcation of traditional and SLE-speciﬁc CVD risk

factors. Presently, in order to lower the CV risk in SLE, the

main objectives should be treating the disease targeting

remission or low disease activity [122] and sparing

cortico-steroids when possible, whilst monitoring traditional CVD

risk factors at least once a year [123].

HCQ should be an essential part of SLE treatment

strategy and should be started as soon as the diagnosis has

been made and maintained for an inde

ﬁnite period if toxicity

does not occur [81]. Although for a long time it has been

considered a minor component in the management of SLE,

in fact, increasing evidence demonstrates that HCQ has a

broad spectrum of beneﬁcial eﬀects on disease activity,

prevention of damage accrual, and mortality [124].

Further-more, HCQ is thought to protect against accelerated

athero-sclerosis by means of several mechanisms of action targeting

both SLE-related and traditional CV risk factors.

One of the main limitations to be considered, when

interpreting the available data, is the lack of a direct

demonstration of the cause-e

ﬀect relationship between

HCQ treatment and atheroprotection from randomized

controlled trials. On the other hand, given the many

evi-dences of bene

ﬁcial eﬀects on HCQ in SLE patients, a

placebo-controlled trial would be probably not ethically

sustainable. Studies addressing the potential eﬀect of HCQ

on CV risk in patients with no existing rheumatic disease

with a very high risk of a recurrent CV event, such as

the OXI trial (NCT02648464), may shed some light on

mechanistic insights regarding the cardioprotective e

ﬀect

of HCQ [125].

In conclusion, despite the lack of randomized controlled

trials, the available evidence strongly suggests that HCQ

exerts bene

ﬁcial eﬀects against atherosclerosis and CVD in

SLE patients.

Conflicts of Interest

The authors declare that there is no conﬂict of interest

regarding the publication of this article.

Authors

’ Contributions

Alberto Floris and Matteo Piga contributed equally to

this work.

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